Human immunodeficiency virus (HIV-1) is the etiologic agent of acquired immunodeficiency syndrome (AIDS). The HIV-1 envelope glycoproteins, gp120 and gp41, play critical roles during virus entry into the target cell, mediating binding to CD4 and the chemokine receptors and the fusion of viral and cellular membranes. The location of the envelope glycoproteins outside of the viral membrane renders these molecules important targets for therapeutic and vaccine development, since they are the only viral components accessible to antibodies. The short half-life of HIV-1-producing cells in infected humans suggests the probable importance of viral cytopathic effect, which is mediated by the viral envelope glycoproteins, to CD4 depletion in vivo. The goal of the proposed work is to understand the structure-function relationships of the HIV-1 envelope glycoproteins important for membrane fusion, a process that contributes to virus entry and cytopathic effect. Specific aims for the extension period of the proposal are: 1. To define precisely the structural basis for the non-covalent association of gpl 20 and gp41 in the unliganded and CD4-bound HIV-1 and SIV envelope glycoproteins; 2. To assess whether a direct relationship exists between CD4 dependency and neutralization resistance, and to define the role of CD4 in HIV-1 entry; 3. To define the structure and function of the V1/V2 variable loops in the context of the HIV-1 envelope glycoprotein trimer; and 4. To understand the role of the chemokine receptors in the virus entry process.transmission and replication.